Antioxidant doping of crosslinked polymers to form non-eluting bearing components

ABSTRACT

Methods provide a non-eluting antioxidant doped UHMWPE in the form of an implant bearing component. The process includes the steps of: (a) providing a preform; (b) irradiating the preform with γ-irradiation to crosslink the UHMWPE; (c) doping the crosslinked preform by exposing it to an antioxidant composition at a temperature below the melting point of the UHMWPE; (d) removing the doped material from contact with the antioxidant composition; and then (e) annealing by heating the doped material at a temperature above 30° C. and below the melting point of the UHMWPE; followed by (f) making an implant bearing component from the doped material, wherein at least 1 mm but no more than about 15 mm of material are removed to make the component.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 60/952,452 filed Jul. 27, 2007, the disclosure of which isincorporated herein by reference.

INTRODUCTION

The present technology relates to antioxidant doping of crosslinkedpolymers. Specifically, the technology relates to processes forincorporating antioxidant materials into crosslinked polymers for use inmedical implants.

Crosslinked polymers such as ultra high molecular weight polyethylene(UHMWPE) have found wide application in medical implants as bearingcomponents. The crosslinked polymers exhibit favorable wear propertiesand have good bio-compatibility. In addition to good wear properties, itis also important to provide materials that resist oxidation so that thelife of the material in the body can be increased.

A variety of techniques has been used to increase the oxidationstability of crosslinked materials such as UHMWPE. In some, a series ofheat treatment steps is performed on the crosslinked material todecrease or eliminate the free radicals induced by the crosslinking.Recently, techniques have been developed to incorporate an antioxidantmaterial such as vitamin E directly into the bulk material.

To incorporate an antioxidant material into a bulk polymer, a challengeis to provide a significant amount of antioxidant in the interior of thematerial while maintaining an acceptable non-leaching value ofantioxidant on the surface. Because polymeric components suitable formaking bearing components in medical implants are relatively large at 2to 3 inches of diameter, extensive soaking times are needed, along withextended periods of annealing or homogenization to incorporate theantioxidant molecule completely into the interior of the bulk polymer.During the extensive soaking times required, it is often observed thatexcess antioxidant is incorporated into the UHMWPE in excess of thesaturation amount. As a result, the antioxidant “sweats” or elutes fromthe doped bulk material.

Improved methods of doping antioxidants into crosslinked polymers inorder to provide non-eluting amounts of antioxidant at the surface wouldbe a significant advance.

SUMMARY

In various embodiments, the present technology provides polymericmaterials such as UHMWPE suitable for use as bearing components inmedical implants. Such implants may be used in hip replacement, kneereplacements, and the like. The polymeric material is preferablycrosslinked to increase its wear properties. The crosslinked polymericmaterial is treated by in-diffusion of antioxidant compositions thatserve to or eliminate trap free radicals in the bulk material. As aresult, the oxidation properties of the crosslinked material areimproved. Antioxidants include, without limitation, vitamin E ortocopherols and carotenoid antioxidants, triazine antioxidants, and thelike.

The present technology provides methods of making a non-elutingantioxidant doped UHMWPE, in the form of an implant bearing component.In an illustrative embodiment, the process includes the steps of: (a)machining a consolidated UHMWPE material or molding nascent UHMWPEpowder to make a preform; (b) irradiating the preform with high energyirradiation such as γ-irradiation to crosslink the UHMWPE; (c) dopingthe crosslinked preform by exposing it to a composition comprising 10%or more by weight of an antioxidant at a temperature below the meltingpoint of the UHMWPE; (d) removing the doped material from contact withthe antioxidant composition; and then (e) annealing by heating the dopedmaterial at a temperature above 30° C. and below the melting point ofthe UHMWPE; followed by (f) making an implant bearing component from thedoped material, wherein at least 1 mm but no more than about 15 mm ofmaterial are removed to make the component; and (g) packaging andsterilizing the bearing component or a medical implant comprising thebearing component, Specific methods include: (a) machining aconsolidated UHMWPE article or molding nascent UHMWPE powder to make apreform; (b) irradiating the preform with γ-irradiation at a dose ofabout 5 to 20 MRad; (c) doping the irradiated preform by submerging itin vitamin E or other antioxidant at a temperature of 100° C. to 130° C.for at least one hour and preferably about 1-24 hours; (d) removing thepreform from the antioxidant and heating for at least an additional hourand preferably 1-400 or greater hours at 100° C. to 130° C.; and then(e) machining the preform to form the final implant component; followedby (f) sterilizing the component by exposing it to γ-irradiation at adose of 1-5 MRad. In some embodiments, methods include making anon-eluting antioxidant doped UHMWPE bearing component manufactured by aprocess comprising steps of: (a) machining a UHMWPE article or moldingUHMWPE powder to make a preform; (b) irradiating the preform to a doseof 5-20 MRad; (c) doping the preform with an antioxidant; (d) machiningthe preform to the shape of the bearing component, while removing from 1mm to 15 mm of material from the preform; and (f) packaging andsterilizing the bearing component.

An advantageous feature of the methods is that non-eluting antioxidantdoped UHMWPE articles are produced. In particular, in variousembodiments, the final components made by the methods are characterizedby antioxidant index at the surface of the component that is less thanthe saturation limit in the component, especially as measured at bodytemperature, while the index throughout the component is above thedetection limit. For vitamin E or α-tocopherol doped UHMWPE, the vitaminE index throughout the component is from 0.01 to 0.2, and is preferablyless than or equal to 0.15. In various embodiments, the antioxidant isvitamin E, α-tocopherol, or a combination of chemical species havingantioxidant properties and providing vitamin E activity. The disclosedmethods provide materials useful and suitable as bearing components forimplantation into the human body, for example as acetabular cups for hipimplants.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows perspective (1 a) and plan (1 b-1 d) views of a preform anda bearing (1 e) produced from the preform.

FIG. 2 is a graph of vitamin E index in an implant component.

DESCRIPTION

The following description of technology is merely exemplary in nature ofthe subject matter, manufacture and use of one or more inventions, andis not intended to limit the scope, application, or uses of any specificinvention claimed in this application or in such other applications asmay be filed claiming priority to this application, or patents issuingtherefrom. The following definitions and non-limiting guidelines must beconsidered in reviewing the description of the technology set forthherein.

The headings (such as “Introduction” and “Summary,”) used herein areintended only for general organization of topics within the presentdisclosure, and are not intended to limit the disclosure of thetechnology or any aspect thereof. In particular, subject matterdisclosed in the “Introduction” may include aspects of technology withinthe scope of a patentable invention, and may not constitute a recitationof prior art. Subject matter disclosed in the “Summary” is not anexhaustive or complete disclosure of the entire scope of the technologyor any embodiments thereof. Similarly, subpart headings in theDescription are given for convenience of the reader, and are not arepresentation that information on the topic is to be found exclusivelyat the heading.

The description and specific examples, while indicating embodiments ofthe present technology, are intended for purposes of illustration onlyand are not intended to limit the scope of any invention. Moreover,recitation of multiple embodiments having stated features is notintended to exclude other embodiments having additional features, orother embodiments incorporating different combinations of the statedfeatures. Specific Examples are provided for illustrative purposes ofhow to make, use and practice the compositions and methods of thistechnology and, unless explicitly stated otherwise, are not intended tobe a representation that given embodiments of this technology have, orhave not, been made or tested.

As used herein, the words “preferred” and “preferably” refer toembodiments of the technology that afford certain benefits, undercertain circumstances. However, other embodiments may also be preferred,under the same or other circumstances. Furthermore, the recitation ofone or more preferred embodiments does not imply that other embodimentsare not useful, and is not intended to exclude other embodiments fromthe scope of the technology.

As used herein, the word “include,” and its variants, is intended to benon-limiting, such that recitation of items in a list is not to theexclusion of other like items that may also be useful in the materials,compositions, devices, and methods of this technology.

The present technology provides a method of incorporating an antioxidantcomposition (for example, one containing vitamin E or an α-tocopherol)into a polymeric bulk material (for example, ultra high molecular eightpolyethylene, or UHMWPE) by a series of doping, irradiation, heating,and machining steps. In various embodiments, the methods arecharacterized by a series of machining, irradiating, doping, packaging,and sterilizing steps. Methods include a final machining step after aUHMWPE preform is doped with antioxidant. In this way, bearingcomponents and other UHMWPE articles are provided that containsignificant amounts of antioxidants such as vitamin E throughout thebulk of the component or material, but which have a non-eluting value ofantioxidant at the surface.

The individual steps are carried out in the order recited in the variousembodiments. Various parameters of each of the steps are describedbelow. It is intended that any of the parameters described forindividual steps can be combined in processes to make suitable bearingimplant components.

Polymers

Preferred polymers for use in the methods of this technology includethose that are wear resistant, have chemical resistance, resistoxidation, and are compatible with physiological structures. In variousembodiments, the polymers are polyesters, polymethylmethacrylate, nylonsor polyamides, polycarbonates, and polyhydrocarbons such as polyethyleneand polypropylene. High molecular weight and ultra high molecular weightpolymers are preferred in various embodiments. Non-limiting examplesinclude high molecular weight polyethylene, ultra high molecular weightpolyethylene (UHMWPE), and ultra high molecular weight polypropylene. Invarious embodiments, the polymers have molecular ranges from approximatemolecular weight range in the range from about 400,000 to about10,000,000.

UHMWPE is used in joint replacements because it possesses a lowco-efficient of friction, high wear resistance, and compatibility withbody tissue. UHMWPE is available commercially as bar stock or blocksthat have been compression molded or ram extruded. Commercial examplesinclude the GUR series from Hoechst. A number of grades are commerciallyavailable having molecular weights in the preferred range describedabove.

Preparation of UHMWPE Starting Materials

Ultra high molecular weight polyethylene useful herein includesmaterials in flake form as are commercially available from a number ofsuppliers. In various embodiments, UHMWPE starting materials areproduced from the powdered UHMWPE polymer by methods known in the art.In one embodiment, a preform UHMWPE is made by molding a nascent UHMWPEpowder to a net shape that is close in dimension to the ultimate implantcomponent so that the latter can be made in the subsequent machiningstep described below.

In another embodiment, a preform is made by machining a consolidatedUHMWPE. For example, the powder can be consolidated and formed intosuitable starting materials by compression molding or RAM extrusion. Inone embodiment, consolidated UHMWPE is provided in the form of cylindersor rods of about 3″ in diameter. Preferred processes for producing aUHMWPE starting material are described in U.S. Pat. No. 5,466,350,England et al., issued Nov. 14, 1995 and U.S. Pat. No. 5,830,396,Higgins et al., issued Nov. 3, 1998, the disclosures of which areincorporated by reference. A preform is then machined from theconsolidated material.

In various embodiments, the consolidated UHMWPE starting material isfirst stress relieved before being subjected to the other stepsdescribed herein. Typically, stress relieving is carried out by heatingthe starting material to a temperature suitably high to effect stressrelief but less than the melting temperature of the starting material.Typical stress relief temperature is from about 100° C. to 130° C.Stress relief is carried out for a suitable amount of time, for examplefrom 1 to 5 hours. After stress relief, the starting material is cooledand subjected to the subsequent machining, crosslinking, doping, andfinal machining steps described herein.

Preform Preparation

In various embodiments, a crosslinked polymeric bulk material is furtherprocessed in a series of doping, heating, cooling, and machining steps.Before crosslinking, a preform UHMWPE is made. In one aspect, aconsolidated UHMWPE starting material is optionally and preferablysubjected to a first machining step to make a preform prior tosubsequent irradiation and further processing. In another aspect, apreform is made by directly compressing or molding a nascent UHMWPEpowder to the preform shape. Directly compressing includes formingsheets of UHMWPE in a range of thicknesses, which are then cut orotherwise shaped into preforms. In both aspects, the UHMWPE preform isgiven a generic shape characterized by dimensions close to those of theultimate bearing component, but greater in each dimension by about 1 toabout 15 mm. The generic shape of the preform can be compared to that ofthe ultimate component by considering an arbitrary line drawn throughthe bulk of the preform from one of its surfaces to another, defining a“dimension” of the preform. After machining of the ultimate component, adimension is considered in the same orientation as that in the preform,again represented by a line drawn from one surface through its bulk toanother surface. It is seen that the line defining the dimension in thecomponent is shorter than the line in the preform, reflecting removal ofmaterial. Further, it is seen that, for any line in the component,material is removed at both ends of the corresponding line in thepreform, and this material removal reflects shortening the line by 1 to15 mm on both ends. The preform is thus made prior to irradiation anddoping in order to permit the second machining step to be carried outwith removal of only a slight amount of material on the outside of thepreform in order to arrive at the ultimate shape of the bearingcomponent. In various embodiments, the preform has a generic shape thatis larger in dimensions by about 1 to about 15 mm than the ultimatebearing component so that the subsequent second machining step removesthe extra 1 to 15 mm of material. In some embodiments, the amount ofextra material in the generic shape is 1-10 mm or 1-4 mm. In variousembodiments, the “extra” material of the preform is provided in auniform thickness around the preform. Thus in illustrative embodiments,the preform is uniformly larger in every dimension by 1 to 15 mm thanthe ultimate bearing component. In such a case, the second machiningstep is carried out to remove the uniform shell of material around thepreform to arrive at the ultimate bearing component.

Alternatively, the “extra” material of the preform can be provided invarying thicknesses, for example from 1 to 15 mm around the preform. Inthis case, the second machining step is carried out to remove theunevenly distributed outside shell material of the preform to arrive atthe shape of the final implant.

Preferably, the preform provided after machining a consolidated UHMWPEor direct molding of a nascent UHMWPE powder has a minimum amount ofextra shell material that is to be subsequently removed in a subsequentmachining step. The exact dimensions and shape of the preform isselected for ease of manufacturing, keeping in consideration thedesirability of removing minimal material in the subsequent machiningstep.

Crosslinking

The polymeric bulk material in the shape of a preform can be crosslinkedby a variety of chemical and radiation methods. In various embodiments,chemical crosslinking is accomplished by combining a polymeric materialwith a crosslinking chemical and subjecting the mixture to temperaturesufficient to cause crosslinking to occur. In various embodiments, thechemical crosslinking is accomplished by molding a polymeric materialcontaining the crosslinking chemical. The molding temperature is thetemperature at which the polymer is molded. In various embodiments, themolding temperature is at or above the melting temperature of thepolymer.

If the crosslinking chemical has a long half-life at the moldingtemperature, it will decompose slowly, and the resulting free radicalscan diffuse in the polymer to form a homogeneous crosslinked network atthe molding temperature. Thus, the molding temperature is alsopreferably high enough to allow the flow of the polymer to occur todistribute or diffuse the crosslinking chemical and the resulting freeradicals to form the homogeneous network. For UHMWPE, a preferredmolding temperature is between about 130° C. and 220° C. with a moldingtime of about 1 to 3 hours. In a non-limiting embodiment, the moldingtemperature and time are 170° C. and 2 hours, respectively.

The crosslinking chemical may be any chemical that decomposes at themolding temperature to form highly reactive intermediates, such as freeradicals, that react with the polymers to form a crosslinked network.Examples of free radical generating chemicals include peroxides,peresters, azo compounds, disulfides, dimethacrylates, tetrazenes, anddivinylbenzene. Examples of azo compounds are: azobis-isobutyronitrile,azobis-isobutyronitrile, and dimethylazodi-isobutyrate. Examples ofperesters are t-butyl peracetate and t-butyl perbenzoate.

In various embodiments the polymer is crosslinked by treating it with anorganic peroxide. Suitable peroxides include2,5-dimethyl-2,5-bis(tert-butylperoxy)-3-hexyne (Lupersol 130, AtochemInc., Philadelphia, Pa.); 2,5-dimethyl-2,5-di-(t-butylperoxy)-hexane;t-butyl α-cumyl peroxide; di-butyl peroxide; t-butyl hydroperoxide;benzoyl peroxide; dichlorobenzoyl peroxide; dicumyl peroxide;di-tertiary butyl peroxide; 2,5-dimethyl-2,5-di(peroxybenzoate)hexyne-3; 1,3-bis(t-butyl peroxy isopropyl) benzene; lauroylperoxide; di-t-amyl peroxide; 1,1-di-(t-butylperoxy) cyclohexane;2,2-di-(t-butylperoxy)butane; and 2,2-di-(t-amylperoxy) propane. Apreferred peroxide is 2,5-dimethyl-2,5-bis(tert-butylperoxy)-3-hexyne.The preferred peroxides have a half-life of between 2 minutes to 1 hour;and more preferably, the half-life is between 5 minutes to 50 minutes atthe molding temperature. Generally, between 0.2 to 5.0 wt % of peroxideis used; more preferably, the range is between 0.5 to 3.0 wt % ofperoxide; and most preferably, the range is between 0.6 to 2 wt %.

The peroxide can be dissolved in an inert solvent before being added tothe polymer powder. The inert solvent preferably evaporates before thepolymer is molded. Examples of such inert solvents are alcohol andacetone.

For convenience, the reaction between the polymer and the crosslinkingchemical, such as peroxide, can generally be carried out at moldingpressures. Generally, the reactants are incubated at moldingtemperature, between 1 to 3 hours, and more preferably, for about 2hours.

The reaction mixture is preferably slowly heated to achieve the moldingtemperature. After the incubation period, the crosslinked polymer ispreferably slowly cooled down to room temperature. For example, thepolymer may be left at room temperature and allowed to cool on its own.Slow cooling allows the formation of a stable crystalline structure.

The reaction parameters for crosslinking polymers with peroxide, and thechoices of peroxides, can be determined by one skilled in the art. Forexample, a wide variety of peroxides are available for reaction withpolyolefins, and investigations of their relative efficiencies have beenreported. Differences in decomposition rates are perhaps the main factorin selecting a particular peroxide for an intended application.

In various embodiments, crosslinking is accomplished by exposing apolymeric bulk material to irradiation. Non-limiting examples ofirradiation for crosslinking the polymers include electron beam, x-ray,and γ-irradiation. In various embodiments, γ-irradiation is preferredbecause the radiation readily penetrates the bulk material. Electronbeams can also be used to irradiate the bulk material. With e-beamradiation, the penetration depth depends on the energy of the electronbeam, as is well known in the art.

For gamma (γ) irradiation, the polymeric bulk material is irradiated ina solid state at a dose of about 0.01 to 100 MRad (0.1 to 1000 kGy),preferably from 1 to 20 MRad, using methods known in the art, such asexposure to gamma emissions from an isotope such as ⁶⁰Co. In variousembodiments, γ-irradiation for a crosslinking is carried out at a doseof 1 to 20, preferably about 5 to 20 MRad. In a non-limiting embodiment,irradiation is to a dose of approximately 10 MRad.

Irradiation of the polymeric bulk material is usually accomplished in aninert atmosphere or vacuum. For example, the polymeric bulk material maybe packaged in an oxygen impermeable package during the irradiationstep. Inert gases, such as nitrogen, argon, and helium may also be used.When vacuum is used, the packaged material may be subjected to one ormore cycles of flushing with an inert gas and applying the vacuum toeliminate oxygen from the package. Examples of package materials includemetal foil pouches such as aluminum or Mylar® coating packaging foil,which are available commercially for heat sealed vacuum packaging.Irradiating the polymeric bulk material in an inert atmosphere reducesthe effect of oxidation and the accompanying chain scission reactionsthat can occur during irradiation. Oxidation caused by oxygen present inthe atmosphere present in the irradiation is generally limited to thesurface of the polymeric material. In general, low levels of surfaceoxidation can be tolerated, as the oxidized surface can be removedduring subsequent machining.

Irradiation such as γ-irradiation can be carried out on polymericmaterial at specialized installations possessing suitable irradiationequipment. When the irradiation is carried out at a location other thanthe one in which the further heating, doping, and machining operationsare to be carried out, the irradiated bulk material is conveniently leftin the oxygen impermeable packaging during shipment to the site forfurther operations.

Doping Methods

In various embodiments, an antioxidant composition is doped into thebulk material to provide antioxidant at an effective level, especiallythroughout the whole bulk of the components. Preferably, the methodsprovide a rapid method of doping to provide effective antioxidantlevels. In this regard, advantage is taken of the preform shape and itsclose approximation to the final dimensions of the component being made.That is, since the preform is only 1-15 mm, 1-10 mm, or 1-4 mm larger inany dimension than the ultimate component, the preforms can be doped ina reasonable amount of time to provide measurable levels of antioxidantthroughout the bulk of the component. Then, any surface of the dopedpreform that is higher in antioxidant than the saturation value can becut off to “expose” a surface having a non-eluting value of antioxidant.In various embodiments, the shape of the preform and the time of dopingand homogenizing are chosen to provide the desired level of antioxidant.

Antioxidant compositions useful herein contain one or more antioxidantcompounds. Non-limiting examples of antioxidant compounds includetocopherols such as vitamin E, carotenoids, triazines, vitamin K, andothers. Preferably, the antioxidant composition comprises at least about10% of one or more antioxidant compounds. In various embodiments, theantioxidant composition is at least 50% by weight antioxidant up to anincluding 100%, or neat antioxidant.

As used here, the term vitamin E is used as a generic descriptor for alltocol and tocotrienol derivatives that exhibit vitamin E activity, orthe biological activity of α-tocopherol. Commercially, vitamin Eantioxidants are sold as vitamin E, α-tocopherol, and related compounds.The term tocol is the trivial designation for2-methyl-2-(4,8,12-trimethyltridecyl)chroman-6-ol (compound I,R¹═R²═R³═H).

The term tocopherol is used as a generic descriptor for mono, di, andtri substituted tocols. For example, α-tocopherol is compound I whereR¹═R²═R³=Me; β-tocopherol is compound I where R¹═R³=Me and R²═H.Similarly, γ-tocopherol and 6-tocopherol have other substitutionpatterns of methyl groups on the chroman-ol ring.

Tocotrienol is the trivial designation of2-methyl-2-(4,8,12-trimethyltrideca-3,7,1,1-trienyl)chroman-6-ol.

Examples of compound II include 5,7,8-trimethyltocotrienol,5,8-dimethyltocotrienol, 7,8-dimethyltocotrienol, and8-methyltocotrienol.

In compound I, there are asymmetric centers at positions 2, 4′, and 8′.According to the synthetic or natural origin of the various tocolderivatives, the asymmetric centers take on R, S, or racemicconfigurations. Accordingly, a variety of optical isomers anddiasteromers are possible based on the above structure. To illustrate,the naturally occurring stereoisomer of α-tocopherol has theconfiguration 2R, 4′R, 8′R, leading to a semi-systematic name of(2R,4′R,8′R)-α-tocopherol. The same system can be applied to the otherindividual stereoisomers of the tocopherols. Further information onvitamin E and its derivatives can be found in book form or on the webpublished by the International Union of Pure and Applied Chemistry(IUPAC). See for example, 1981 recommendations on “Nomenclature ofTocopherols and Related Compounds.”

Carotenoids are a class of hydrocarbons (carotenes) and their oxygenatedderivatives (xanthophylls) consisting of eight isoprenoid units joinedin such a manner that the arrangement of isoprenoid units is reversed atthe center of the molecule. As a result, the two central methyl groupsare in a 1,6-positional relationship and the remaining nonterminalmethyl groups are in a 1,5-positional relationship. The carotenoids areformally derived from an acyclic C₄₀H₅₆ structure having a long centralchain of conjugated double bonds. The carotenoid structures are derivedby hydrogenation, dehydrogenation, cyclization, or oxidation, or anycombination of these processes. Specific names are based on the namecarotene, which corresponds to the structure and numbering shown incompound III.

The broken lines at the two terminations represent two “double bondequivalents.” Individual carotene compounds may have C₉ acyclic endgroups with two double bonds at positions 1,2 and 5,6 (IV) or cyclicgroups (such as V, VI, VII, VIII, IX, and X).

The name of a specific carotenoid hydrocarbon is constructed by addingtwo Greek letters as prefixes to the stem name carotene. If the endgroup is acyclic, the prefix is psi (ψ), corresponding to structure IV.If the end group is a cyclohexene, the prefix is beta (β) or epsilon(ε), corresponding to structure V or VI, respectively. If the end groupis methylenecyclohexane, the designation is gamma (γ), corresponding tostructure VII. If the end group is cyclopentane, the designation iskappa (κ), corresponding to structure VIII. If the end group is aryl,the designation is phi (φ) or chi (χ), corresponding to structures IXand X, respectively. To illustrate, “β-carotene” is a trivial name givento asymmetrical carotenoid having beta groups (structure V) on bothends.

Elimination of a CH₃, CH₂, or CH group from a carotenoid is indicated bythe prefix “nor”, while fusion of the bond between two adjacent carbonatoms (other than carbon atoms 1 and 6 of a cyclic end group) withaddition of one or more hydrogen atoms at each terminal group thuscreated is indicated by the prefix “seco”. Furthermore, carotenoidhydrocarbons differing in hydrogenation level are named by use of theprefixes “hydro” and “dehydro” together with locants specifying thecarbon atoms at which hydrogen atoms have been added or removed.

Xanthophylls are oxygenated derivatives of carotenoid hydrocarbons.Oxygenated derivatives include without limitation carboxylic acids,esters, aldehydes, ketones, alcohols, esters of carotenoid alcohol, andepoxies. Other compounds can be formally derived from a carotenoidhydrocarbon by the addition of elements of water (H, OH), or of alcohols(H, OR, where R is C₁₋₆ alkyl) to a double bond.

Carotenoids having antioxidant properties are among compounds suitablefor the antioxidant compositions of the invention. Non-limiting examplesof the invention include vitamin A and beta-carotene.

Other antioxidants include vitamin C (absorbic acid) and itsderivatives; vitamin K; gallate esters such propyl, octyl, and dodecyl;lactic acid and its esters; tartaric acid and its salts and esters; andortho phosphates. Further non-limiting examples include polymericantioxidants such as members of the classes of phenols; aromatic amines;and salts and condensation products of amines or amino phenols withaldehydes, ketones, and thio compounds. Non-limiting examples includepara-phenylene diamines and diaryl amines.

Antioxidant compositions preferably have at least 10% by weight of theantioxidant compound or compounds described above. In preferredembodiments, the concentration is 20% by weight or more or 50% by weightor more. In various embodiments, the antioxidant compositions areprovided dissolved in suitable solvents. Solvents include organicsolvents and supercritical solvents such as supercritical carbondioxide. In other embodiments, the antioxidant compositions containemulsifiers, especially in an aqueous system. An example is vitamin E(in various forms such as α-tocopherol), water, and suitable surfactantsor emulsifiers. In a preferred embodiment, when the antioxidant compoundis a liquid, the antioxidant composition consists of the neat compounds,or 100% by weight antioxidant compound.

During the doping process, the bulk material is exposed to antioxidantin a doping step followed by heat treatment or homogenization out ofcontact with the antioxidant. Total exposure time of the bulk materialto the antioxidant is selected to achieve suitable penetration of theantioxidant. In various embodiments, total exposure time is at leastseveral hours and preferably greater than or equal to one day (24hours).

In various embodiments, a doping step is followed by a subsequentannealing or “homogenization” step. In one aspect, it is desirable toprovide methods of achieving a suitable level of antioxidant in theinterior or inner portions of the bulk material, while avoiding excessantioxidant at the outer surface. During the homogenization step, theantioxidant continues to diffuse into the interior of the bulk material.In various embodiments, the total time of annealing or homogenization isat least several hours and more preferably more than one day. Forexample, while there is no particular upper limit, homogenization ispreferably carried out for at least an hour after doping, and typicallyfor a period of 1 to about 400 or about 500 hours. Depending on the sizeof the part, the post doping heating is carried out for a period of 10to 14 days, or for 11 to 17 days, by way of non-limiting example. In thecase of vitamin E, the vitamin E index is preferably greater than orequal to about 0.01 in the center and throughout the bulk of thecomponent, while being less than the saturation level on the outside ofsurface. The saturation level on the outside surface is normally takento be the saturation level of the antioxidant in the component at bodytemperature, which is the approximate temperature to which the implantwill be exposed when implanted. Body temperature takes on a range ofvalues, but “normal” human body temperature is commonly referred to as98.6° F., which converts to 37° C.

The temperature at which the exposing (doping) and annealing(homogenization) steps are carried out is preferably as high as possiblebut below the crystalline melting point of the material to avoiddestroying the strength of the material. This is particularly usefulwhen the material is to be used as a bearing component for a medicalimplant. In various embodiments, the temperature of exposure andannealing is carried out at or above 30° C., at or above 50° C., at orabove 80° C., at or above 100° C., and at or above 120° C. Preferably,the temperature is below the melting point of the bulk polymer.Preferred temperatures, especially for the case of UHMWPE, include lessthan or about 135° C. and less than or about 130° C. In a preferredembodiment, UHMWPE is exposed and annealed (homogenized) at atemperature of about 130° C.

The doping and homogenization steps can be repeated as desired toachieve suitable dispersion of the antioxidant through the bulk preform.In various embodiments, breaking up the time of exposure to antioxidantand the time of homogenization into two or more periods provides greaterdiffusion of the antioxidant into the interior of the bulk material thanthe same amount of time of exposure in one dose. At the same time, themethod tends to avoid an accumulation of antioxidant on the surface ofthe bulk material, which could lead to undesirable exudation or“sweating” of the bulk material, as excess antioxidant rises to thesurface and escapes from the bulk. Furthermore, without limiting thescope, function or utility of the present technology, it is believedthat the sequential doping method provide additional “driving force” forthe diffusion of antioxidant into the interior of the bulk material. Thedriving force is proportional to the concentration difference orgradient of the antioxidant such as α-tocopherol on the surface andinside the bulk of the polymeric material. As the antioxidant diffusesinto the bulk, the driving force is reduced. In various embodiments, themethods of the invention counteract the reduced driving force byrecharging it periodically with sequential doping of the antioxidant.

In various embodiments, the sequence of steps constituting adoping/removing/heating cycle is carried out 2, 3, 4, or more times asdesired to provide the desired level of doping of antioxidant.Preferably, the total time of exposure of the polymeric bulk material tothe antioxidant during the plurality of doping cycles is at leastseveral hours, preferably greater than one day and preferably greaterthan two days, up to 3 weeks, 2 weeks, or one week when held for exampleat about 130° C. The total time of annealing or homogenization when outof contact with the antioxidant composition is preferably at leastseveral hours over the plurality of cycles. Preferably, the annealingtime is greater than one day and preferably greater than two days, up toone week, two weeks, or three weeks of total annealing time during thecycles. During the annealing steps when out of contact, the antioxidantfurther diffuses into the interior of the bulk material.

In a particular embodiment, the present technology provides a method ofmaking an oxidation resistant UHMWPE by exposing a polymeric material toan antioxidant composition comprising vitamin E. The method involvesexposing a bulk crosslinked UHMWPE to a composition comprising vitamin Eat a temperature below the crystalline melting point of the UHMWPE.Thereafter, the bulk UHMWPE is removed from exposure to the vitamin Ecomposition and is annealed by heating it to a temperature greater than30° C. and below the melting point. The exposing and annealing steps canbe repeated at least once, preferably until the vitamin E index measuredthroughout the preform is at least 0.01 while the vitamin E index on theoutside surface of the bar preferably remains less than the saturationvalue. The vitamin E index throughout the preform preferably is in therange of 0.01 to 0.2, or 0.01 to 0.15, or 0.01 to 0.10. In this andother embodiments, it is understood that removing the UHMWPE fromexposure to the vitamin E composition encompasses either removing thebar physically from the composition or removing the composition whileleaving the bar in place. Combinations of the two methods may also beused. It is further understood that exposing the bulk material to theantioxidant composition can involve either plunging the bulk materialinto the composition or pouring the composition onto the bar to coverit. As before, combinations of the two may also be used.

Machining to the Final Shape of the Implant Component

A machining step is carried out to produce a UHMWPE material in theshape of the ultimate bearing component. As noted, the step is used toremove a fairly small amount of material, illustratively from 1 to 15mm, 1 to 10 mm, or 1 to 4 mm from the preform that was crosslinked, andthen doped with antioxidant. Advantageously, the dimensions of thepreform can be selected so that, depending on demand, a number ofdifferent implant components or sizes of implant components can bemachined from the preform. Thus for example, it is possible to make andstockpile a supply of preforms, and produce implant components as neededin the sizes required. The machining step removes an outer surface orlayer of the preform. This may provide the further advantage of removingan eluting outer layer of the preform that might have produced duringthe doping and homogenizing steps.

Non-limiting examples of implant components include tibia bearings,acetabular linings, glenoid components of an artificial shoulder, andspinal components such as those used for disk replacement or in a motionpreservation system.

Products of the Methods

In various embodiments, the methods provide bulk materials especially inthe form of a medical implant bearing components having significantlevels of antioxidants throughout the interior of the bulk material. Ina preferred embodiment, the implants have a level of antioxidant that isbelow the saturation level at which sweating or eluting of antioxidantwould be observed. When the antioxidant is based on the tocopherolmolecule (vitamin E) the vitamin E index in the interior of thecomponents is at least 0.01, and is preferably greater than 0.02, whilethe vitamin E index on the exterior (i.e. at points close to or on thesurface) is preferably less than or equal to 0.2.

Vitamin E index is measured from infrared absorbent experiments carriedout on thin sections of doped material. Absorbance due to vitamin Ebetween 1226 and 1275 cm⁻¹ is integrated and compared to a referenceabsorbance peak located between about 1850 and 1985 cm⁻¹. The ratio ofthe two peaks is the vitamin E index. The vitamin E index has adetectable level of about 0.008 or 0.01.

Experimentally, suitable vitamin E doping can be determined by measuringthe index at a point in the interior of the preform or of the componentthat is the farthest from a surface of the respective solid. If theindex at a point farthest from the surface is above a minimum value,then other points in the component closer to the surface are expected tohave at least that index or higher. Similarly, the measured index on thesurface is likely to be a maximum, so that no interior point of thecomponent will have an index higher than that measured on the surface.These considerations follow from the fact that the antioxidant isdiffused into a bulk preform from outside. During doping, the durationof which is dependent on the size of the preform, the antioxidantdiffuses from the exterior surface into the interior. When the interiorof the preform reaches a vitamin E index of at least 0.01 and preferablyat least 0.02, the preform is ready for the subsequent steps describedherein. In preferred embodiments, the exterior vitamin E index of thefinished part is lower than that which causes the vitamin E in thecomponent to sweat or elute from the surface, even though the preformfrom which the part is made exhibits a surface or exterior index thatcauses it to noticeably sweat or elute.

In the case of γ-crosslinked UHMWPE, the doped polymeric bulk materialcontains a measurable level of free radicals resulting from theγ-irradiation and crosslinking. Nevertheless, without limiting thescope, function or utility of the present technology, it is believedthat the free radicals are associated in the bulk material withantioxidant molecules. As a result, the doped bulk material is resistantto oxidation, exhibiting an oxidation index increase of less than 0.5when exposed to oxygen at 70° C. for four weeks. Preferably, theoxidation index increases less than 0.2, or less than 0.1. In preferredembodiments, the oxidation index essentially does not change duringexposure to oxygen at elevated temperatures for times up to four weeks.

In general, the free radical concentration in the polymer changes as thevarious process steps are carried out. The consolidated UHMWPE startingmaterial and the nascent UHMWPE powder contain essentially no freeradicals. The unirradiated preforms likewise have essentially nodetectable free radicals. On crosslinking, the free radicalconcentration grows to a significant level, which is slightly reducedwhen the irradiated preform is doped with antioxidant. The level ofdetectable free radicals is further significantly reduced during thepost doping heat treatment, annealing, or homogenizing step. The finalmachining step has little effect on free radicals, while the finalirradiation sterilization increases free radicals slightly.Non-irradiative sterilization has no effect on free radicals. Butthroughout, the free radicals are not reduced to non-detectable levelsat any time after the irradiation. This is in contrast to crosslinkedmaterials that have been heated or even melted to recombine freeradicals and reduce their concentration. But despite the relativelyhigher concentration of free radicals, antioxidant-doped crosslinkedpolymers of the invention maintain a high resistance to oxidation,which, without limiting the scope, function or utility of the presenttechnology, is believed to be attributable to a sequestration of thefree radicals in close association with the antioxidant compounds.

Oxidation index is calculated by measuring the infrared absorbance ofthe carbonyl band at about 1740 cm⁻¹ and comparing it to the methylenevibration at about 1370 cm⁻¹. The methylene vibration absorbentscorrects for the thickness of the test sample. In a preferredembodiment, oxidation index measurement and calculations are based onASTM F 2102-01. Oxidation peak area is the integrated area below thecarbonyl peak between 1650 and 1850 cm⁻¹. The normalization peak area isthe integrated area below the methylene stretch between 1330 and 1396cm⁻¹. Oxidation index is calculated by dividing the oxidation peak areaby the normalization peak area.

In various embodiments, implant bearing components are manufactured frompolymeric starting materials using the methods described herein.Non-limiting examples of bearing components include those in hip joints,knee joints, ankle joints, elbow joints, shoulder joints, spine,temporo-mandibular joints, and finger joints. In hip joints, forexample, the methods can be used to make the acetabular cup or theinsert or liner of the cup. In the knee joints, the compositions can bemade used to make the tibial plateau, the patellar button, and trunnionor other bearing components depending on the design of the joints. Inthe ankle joint, the compositions can be used to make the talar surfaceand other bearing components. In the elbow joint, the compositions canbe used to make the radio-numeral or ulno-humeral joint and otherbearing components. In the shoulder joint, the compositions can be usedto make the glenero-humeral articulation and other bearing components.In the spine, intervertebral disc replacements and facet jointreplacements may be made from the compositions.

The methods described herein provide additional benefits to themanufacturing process. When doping is carried out on a finishedcomponent, growth and shrinkage of the UHMWPE observed upon addition ofantioxidant can cause the geometry to change significantly. On the otherhand, machining the final component from a near net shape preform asdescribed herein produces a product that is dimensionally accurate anddimensionally stable. The machining step thus eliminates a variable andmakes the process more predictable.

The materials, methods and devices of the present technology are furtherexemplified by the following non-limiting examples.

EXAMPLES Example 1

FIG. 1 a shows a perspective view of a tibial preform 10 characterizedby an overall kidney shape and containing two non-through holes 20. FIG.1 b shows a plan view of the top of the preform 10. Hidden linesindicate schematically the rough position of a tibial bearing 30 to bemachined out of the preform 10. FIG. 1 c is a plan view showing thedepth 40 of the non-through holes 20 and the height 50 and length 60 ofthe preform 10. FIG. 1 d is another side plan view showing thenon-through holes 20 and the hidden lines of the tibial bearing 30. FIG.1 e is a perspective of the tibial bearing 30 prepared by machining thepreform.

The views of FIG. 1 illustrate the preform in relation to the implantcomponent machined from it. A line from the surface 70 of the preform tothe component 30, when drawn in its shortest length, will be, in variousembodiments, 1-15 mm, 1-10 mm, or 1-4 mm in length. Put another way, theouter surface of the component is within 15 mm of the outer surface ofthe preform.

Example 2

Preparing an implant component involves the following steps:

An acetabular preform is machined from UHMWPE barstock. A typicalpreform is shown in FIG. 1 a.

The preform is then cleaned in isopropyl alcohol, placed in a barrierfilm bag, the bag is placed in a chamber which evacuates the air, purgeswith argon, evacuates the argon and then seals the package.

The preforms are then boxed in a double layer and sent for gammairradiation to a dose of 100±10 kGy.

When the preforms return, they are removed from the barrier filmpackaging and doped in vitamin E (dl-α-tocopherol) for 8 hours at 122°C.

At the end of the doping cycle, the excess vitamin E is cleaned from thesurface.

The preforms are then placed in an inert gas oven and heated to 130° C.and the temperature is held for 264 hours. At the end of the 264 hours,the oven is cooled to room temperature over 6 hours.

FTIR testing is used to quantify the amount of vitamin E in thepolyethylene where the diffusion distance is a maximum. The minimumvitamin E index is 0.02.

The preform is then machined into a liner by removing a minimum of 1.5mm of material from all surfaces of the pre-form.

The liners are then laser etched with the lot number, cleaned inisopropyl alcohol, barrier film packaged with an argon purge, blisterpacked, and boxed and labeled.

The components are then sent for gamma sterilization with a dose of25-40 kGy.

A typical vitamin E profile taken after this step is shown in FIG. 2.For example, the vitamin E index in an acetabular cup is measured in aline from the inner diameter to the outer diameter, according to theprocedure of Example 3.

Example 3

Equipment for measuring vitamin E or other antioxidant index includes anFTIR spectrometer, a microtome capable of 200 μm thick slices, an irmicroscope with automated stage, and computer software capable ofcollecting spectra across a sample and creating a profile of peak arearatios for two specific peaks. Measuring the index of a part such as animplant component or a preform involves the following steps:

-   -   1. Cut the part such that the area farthest from all surfaces is        exposed. This will be the area with the lowest concentration of        vitamin E.    -   2. Use the microtome to make a 200 μm thick slice of the        preform. The cut direction is perpendicular to the measurement        direction. (The measurement direction is generally the shortest        distance between two surfaces that passes through the area with        the lowest vitamin E concentration.)    -   3. Secure the sample to a slotted metal slide with magnets such        that the measurement direction is parallel to the slot.    -   4. Place the slide in the microscope such that the measuring        direction is parallel to the X-axis of the microscope.    -   5. Using the mapping tool on the FTIR software, create a mapping        line from one surface of the sample to the other along the        measurement direction.    -   6. Collect spectra at 200 μm intervals along the mapping line.    -   7. Use the software to create a profile along the mapping line        of the ratio of the peak area of the vitamin E peak (1245-1275)        to the peak area of the polyethylene peak (1850 to 1985). The        resulting profile shows the vitamin E index through the area of        the polyethylene that is the farthest distance from all        surfaces.

The examples and other embodiments described herein are exemplary andnot intended to be limiting in describing the full scope of devices andmethods of this technology. Equivalent changes, modifications andvariations of specific embodiments, materials, devices and methods maybe made within the scope of the present technology, with substantiallysimilar results.

1. A process of making a non-eluting antioxidant doped UHMWPE, in theform of an implant component having a bearing surface, the processcomprising: (a) machining a consolidated UHMWPE material to make amachined preform or molding nascent UHMWPE powder to make a moldedpreform; (b) irradiating the preform with high energy radiation tocrosslink the UHMWPE; (c) doping the crosslinked machined preform byexposing it to a composition comprising 10% or more by weight of anantioxidant at a temperature below the melting point of the UHMWPE; (d)removing the doped material from contact with the antioxidantcomposition; and then (e) heating the doped material at a temperatureabove 30° C. and below the melting point of the UHMWPE; followed by (f)making an implant component from the doped material by machining thepreform; and (g) packaging and sterilizing the implant component.
 2. Amethod according to claim 1, wherein the high energy radiation is gammairradiation.
 3. A method according to claim 1, wherein the antioxidantcomprises a compound or compounds having vitamin E activity.
 4. A methodaccording to claim 1, wherein the antioxidant comprises α-tocopherol. 5.A method according to claim 1, wherein the antioxidant compositioncomprises a carotenoid.
 6. A method according to claim 1, wherein theantioxidant comprises vitamin A.
 7. A method according to claim 1,wherein the antioxidant comprises vitamin K.
 8. A method according toclaim 1, wherein the antioxidant composition is 100% by weightantioxidant.
 9. A method according to claim 1, wherein the doping stepis carried out as a temperature from 100° C. to 140° C.
 10. A methodaccording to claim 1, wherein making the implant component comprisesremoving at least 1 mm of material and less than or equal to 15 mm ofmaterial to form the implant component.
 11. A method of incorporating anon-eluting amount of α-tocopherol into UHMWPE to make an implantcomponent having a bearing surface, the method comprising: (a) machininga consolidated UHMWPE or molding nascent UHMWPE powder to make apreform; (b) irradiating the preform with high energy radiation to adose of 5 to 20 MRad; (c) doping the irradiated preform by exposing itto an antioxidant composition comprising α-tocopherol at a temperaturegreater than 30° C. and below the crystalline melting point of theUHMWPE; (d) removing the doped preform from exposure to the antioxidantcomposition; and then (e) homogenizing the doped preform by heating at atemperature above 30° C. and below the melting point of the UHMWPE;followed by (f) making the implant component from the doped preform bymachining greater than or equal to 1 mm of material but less than orequal to 15 mm from the doped preform to make the implant component, and(g) packaging and sterilizing the implant component.
 12. A methodaccording to claim 11, wherein the high energy radiation is gammaradiation.
 13. A method according to claim 11, wherein the dose ofgamma-irradiation is 6.5 MRad or greater.
 14. A method according toclaim 11, wherein the doping is carried out at a temperature of 100° C.to 130° C.
 15. A method according to claim 11, wherein the homogenizingstep is carried out at a temperature of 100° C. to 130° C.
 16. A methodaccording to claim 11, wherein the antioxidant comprises greater than orequal to 50% by weight of α-tocopherol.
 17. A method according to claim11, wherein the antioxidant composition is 100% by weight α-tocopherol.18. A method according to claim 11, wherein the implant component ischaracterized by a vitamin E index at the bearing surface of thecomponent that is less than the saturation limit of vitamin E in thecomponent at body temperature.
 19. A method of making a non-elutingoxidation-resistant medical implant component comprising UHMWPE andvitamin E, the method comprising: (a) machining a consolidated UHMWPEarticle or molding a UHMWPE powder to make a preform; (b) irradiatingthe preform with γ-irradiation at a dose of about 1 MRad to about 20MRad; (c) doping the irradiated preform by submerging it in vitamin E ata temperature of 100° C. to 130° C. for at least one hour; (d) removingthe preform from the vitamin E and heating for at least an additionalhour at 100° C. to 130° C.; and then (e) machining the preform to formthe implant component; followed by (f) sterilizing the implant componentby exposing it to γ-irradiation at a dose of 1-4 MRad.
 20. A methodaccording to claim 19, wherein the implant component is characterized bya vitamin E index at the surface of the component that is less than thesaturation limit of vitamin E in the component at body temperature. 21.A method according to claim 19, wherein the vitamin E index throughoutthe component is 0.01 or higher, and less than or equal to 0.2
 22. Amethod according to claim 21, wherein the vitamin E index throughout andon the surface is less than or equal to 0.15.
 23. A method according toclaim 21, wherein the vitamin E index throughout and on the surface isless than or equal to 0.10
 24. A method according to claim 19, whereinthe vitamin E comprises α-tocopherol.
 25. A method according to claim19, comprising doping the irradiated preform in vitamin E for 1-24 hoursand heating for an additional 1-400 hours after removing the preformfrom the vitamin E.
 26. A non-eluting antioxidant doped UHMWPE bearingcomponent manufactured by a process comprising steps of: (a) providing aUHMWPE preform; (b) irradiating the preform at a dose of 5 to 20 MRad ofgamma irradiation; (c) doping the preform with an antioxidant comprisingα-tocopherol; (d) annealing the doped preform below its melting point;(e) machining the preform to the shape of the bearing component, whereinfrom 1 to 15 mm of material is removed from the preform to make thecomponent; and (f) packaging and sterilizing the bearing component. 27.A bearing component according to claim 26, made by irradiating thepreform to a dose of approximately 10 MRad.
 28. A bearing componentaccording to claim 26, wherein the vitamin E index throughout thecomponent is 0.01 or greater, and 0.2 or less.
 29. A bearing componentaccording to claim 28, wherein the vitamin E index throughout thecomponent is 0.15 or less.
 30. A bearing component according to claim28, characterized by having a vitamin E index at the surface of thecomponent that is less than the saturation limit of vitamin E in thecomponent at body temperature.
 31. A medical implant bearing componentmade of crosslinked UHMWPE comprising vitamin E, wherein the vitamin Eindex of the bearing component is at least 0.02 throughout its volumeand the vitamin E index at the outer surface of the bearing component isless than 0.2.